The long-term goals of this study are to understand the cellular and molecular events that occur following perinatal hypoxic-ischemic (H/I) injury and to develop strategies that may reduce or prevent permanent neurologic sequelae. Following perinatal H/I, DNA damage occurs as the result of formation of nitric oxide and reactive oxygen species. The cellular response to this injury involves the activation of multiple metabolic pathways, including the activation of poly(ADP-ribose) polymerase (PARP) and caspases. The activation of PARP-1 after perinatal H/I results in cell death by both necrosis and apoptosis. Oxygen therapy is always given empirically to infants who are suspected of having perinatal H/I injury, but the effects of hyperoxia on the molecular and cellular response to injury are unknown. This project has four major Aims. 1) We will define the chronologic sequence and modes of cell death in neurons and oligodendrocytes after cerebral H/I + hyperoxia in the seven day old rat model, using light microscopy, immunohistochemistry, in situ assessment of DNA damage, and electron microscopy. 2) We will determine the time course and cellular localization of PARP expression, activity, and inactivation by cleavage after H/I +/- hyperoxia using immunohistochemistry and Western blot techniques. 3) We will determine if pharmacological inhibition of PARP alters the quantity and mode (apoptosis vs. necrosis) of neuronal and oligodendrocyte death after perinatal H/I +/- hyperoxia using light microscopic methods as in Aim 1 and assessment of DNA damage by in situ and quantitative PCR methods. 4) We will determine if inhibition of PARP alters long-term neurobehavioral and histological outcome after perinatal H/I +/- hyperoxia and if serial MRI is useful in predicting outcome.